Recent evidence suggests that the primary cause of Alzheimer's disease is the progressive accumulation of neurotpxic oligomeric assemblies of the Abeta 1-42 protein. These neurotoxic oligomeric species are known as ADDLs (Ab-derived diffusible ligands). In Tg2576 AD mice, a transgenic Alzheimer's disease animal model, memory performance declines as ADDL levels increase. Human patients with Alzheimer's disease show a 70-fold elevation in ADDL levels relative to unaffected age-matched controls. ADDLs affect memory by directly interfering with synaptic function, which eventually results in synaptic loss over time. This evidence suggests that small molecule, ADDL-directed therapeutics might prevent ADDL-induced cognitive deficits, and slow or reverse disease progression in humans. This stands in contrast to current FDA-approved drugs, which treat the symptoms and not the underlying cause of Alzheimer's disease. The most promising approach to ADDL-directed therapeutics is to prevent ADDL formation by blocking assembly of the Abeta 1-42 protein. The subject of this proposal is to establish and validate a cascade of primary and secondary chemical screens and screen a representative CNS targeted chemical library to identify small molecules that block ADDL assembly. In Phase I, we propose to develop and validate a homogeneous ADDL assembly blocker screening assay, conduct molecular dynamics simulations to build an ADDL structural model, and carry out pilot screening of a selected small molecule library.